The present invention relates to compounds with activity as antagonists at metabotropic gluatmate receptors and more particularly to pyrazine and triazine derivatives of 1,2,4,5-tetrahydro-Benzo or Thieno [d]azepine that demonstrate activity as group I mGluR antagonists.
In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor. L-glutamic acid, the most commonly occurring neurotransmitter in the CNS, plays a critical role in a large number of physiological processes. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein-coupled receptors.
At present, eight different members of these mGluRs are known and of these some even have sub-types. On the basis of structural parameters, the different second messenger signaling pathways and the different affinity to low-molecular weight chemical compounds, these eight receptors can be sub-divided into three sub-groups: mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.
Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as epilepsy, stroke, chronic and acute pain, psychosis, schizophrenia, Alzheimer""s disease, cognitive disorders and memory deficits. Other treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are Huntington""s chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by pharmaceutical compositions as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depression.
The present invention is a compound of the formula 
wherein
R1 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, or unsubstituted phenyl or phenyl substituted in meta or para position with at least one substituents selected from the group consisting of lower alkyl, lower alkoxy or halogen, or is absent, in the case when X is xe2x80x94Nxe2x95x90 or xe2x95x90Nxe2x80x94;
R2 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, xe2x95x90O, xe2x80x94S-lower alkyl, xe2x80x94SO2-lower alkyl or xe2x80x94OR, xe2x80x94O(CHRa)m+1xe2x80x94ORb, NRc2, NHNRd2, xe2x80x94N(Re)(CHRf)m+1xe2x80x94ORg, xe2x80x94N(Rh)(CHRi)m-pyridino, xe2x80x94N(Rj)(CHRk)nxe2x80x94(C3-C6)cycloalkyl, xe2x80x94N(Rl)(CHRm)m(CRn2)xe2x80x94NRo2, or xe2x80x94N(Rp)(CHRq)m+1xe2x80x94NHxe2x80x94C(O)xe2x80x94O-lower alkyl;
m is 1, 2, 3, 4, 5 or 6;
n is 0, 1, 2, 3, 4 or 5;
R and Ra-q are independently selected from the group consisting of hydrogen, lower alkyl or lower alkenyl;
X is selected from the group consisting of xe2x80x94Nxe2x95x90, xe2x95x90Nxe2x80x94,  greater than Cxe2x95x90 or xe2x95x90C less than ; and, in the case where R2 is xe2x95x90O or alkenyl, the dotted line is a bond,
Y is selected from the group consisting of xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CR3xe2x80x94, xe2x80x94CR3xe2x95x90CHxe2x80x94, xe2x80x94CR3xe2x80x94CR4xe2x80x94 or s; and
R3, R4 are selected, independently from each other, from the group consisting of hydrogen, lower alkyl, lower alkoxy or halogen with the proviso, that when Y represents a vinylene group, only one group R3 and one group R4 are present in the resultant benzene ring;
or a pharmaceutically acceptable salt thereof in racemic and optically active form.
It has surprisingly been found that the compounds of formula I are antagonists at metabotropic glutamate receptors.
Objects of the present invention are compounds of formula I and pharmaceutically acceptable salts thereof and their use as pharmaceutically active substances. Methods for the preparation of the above mentioned substances and pharmaceutical compositions based on compounds in accordance with the invention and their production are also objects of the present invention as well as the use of the compounds in accordance with the invention in the control or prevention of illnesses treated by modulation of metabotropic glutamate receptors, and, respectively, for the production of corresponding pharmaceutical compositions.
Preferred compounds of formula I within the scope of the present invention are those having the formula 
wherein
R1 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, or unsubstituted phenyl or phenyl substituted in meta or para positions with at least one substituent selected from the group consisting of lower alkyl, lower alkoxy or halogen, or is absent, when X is xe2x80x94Nxe2x95x90 or xe2x95x90Nxe2x80x94;
R2 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, xe2x95x90O, xe2x80x94S-lower alkyl,
xe2x80x83xe2x80x94SO2-lower alkyl or
xe2x80x83xe2x80x94OR, xe2x80x94O(CHRa)m+1xe2x80x94ORb, xe2x80x94NRc2, xe2x80x94NHxe2x80x94NRd2, xe2x80x94N(Re)(CHRf)m+1xe2x80x94ORg, xe2x80x94N(Rh)(CHRi)m-pyridino, N(Rj)(CHRk)nxe2x80x94(C3-C6)cycloalkyl, xe2x80x94N(Rl)(CHRm)m(CRn2)NRo2, or xe2x80x94N(Rp)(CHRq)m+1xe2x80x94NHxe2x80x94C(O)xe2x80x94O-lower alkyl;
m is 1, 2, 3, 4, 5 or 6;
n is 0, 1, 2, 3, 4 or 5;
R and Ra-q are independently selected from the group consisting of hydrogen, lower alkyl or lower alkenyl;
X is selected from the group consisiting of xe2x80x94Nxe2x95x90, xe2x95x90Nxe2x80x94,  greater than Cxe2x95x90 or xe2x95x90C less than ; the dotted line is a bond when R is xe2x95x90O or lower alkenyl; and
a pharmaceutically acceptable salt thereof in racemic and optically active form.
Preferred compounds of formula I-A within the scope of the present invention are those, in which
R1 is absent and X is xe2x80x94Nxe2x95x90 or xe2x95x90Nxe2x80x94; and
R2 is xe2x80x94NRc2, xe2x80x94NHxe2x80x94NRd2, xe2x80x94N(Re)(CHRf)m+1xe2x80x94ORg,
xe2x80x94N(Rh)(CHRl)m-pyridino, xe2x80x94N(Rj)(CHRk)nxe2x80x94(C3-C6)cycloalkyl,
xe2x80x94N(Rl)(CHRm)m(CRn2)NRo2, or xe2x80x94N(Rp)(CHRq)m+1xe2x80x94NHxe2x80x94C(O)xe2x80x94O-lower alkyl.
The following are examples of such compounds:
3-Amino-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile,
3-(cyclopropylmethyl-amino)-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile,
3-(2-hydroxy-ethylamino)-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile,
(RS)-3-(2-hydroxy-propylamino)-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile,
3-hydrazino-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile,
{2-[6-cyano-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazin-3-ylamino]-ethyl}-carbamic acid tert-butyl ester, or
3-(2-pyridin-3-yl-ethylamino)-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile.
Especially preferred are those compounds of formula I-A, in which
R1 is absent and X is xe2x80x94Nxe2x95x90 or xe2x95x90Nxe2x80x94; and
R2 signifies xe2x80x94N(Re)(CHRf)m+1xe2x80x94ORg,
xe2x80x94N(Rh)(CHRi)m-pyridino, or xe2x80x94N(Rj)(CHRk)nxe2x80x94(C3-C6)cycloalkyl.
Examples of such compounds are the following:
3-(cyclopropylmethyl-amino)-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile,
3-(2-hydroxy-ethylamino)-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile,
(RS)-3-(2-hydroxy-propylamino)-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile, or
3-(2-pyridin-3-yl-ethylamino)-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile.
Compounds of formula I, in which
X signifies  greater than Cxe2x95x90 or xe2x95x90C less than  and R1 and R2 are lower alkyl, are also preferred.
The following are examples of such compounds:
5-ethyl-6-methyl-3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-pyrazine-2-carbonitrile, or
6-ethyl-5-methyl -3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-pyrazine-2-carbonitrile.
Especially preferred are such compounds of formula I, in which
X signifies  greater than Cxe2x95x90 or xe2x95x90C less than  and R1 signifies ethyl.
6-Ethyl-5-methyl-3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-pyrazine-2-carbonitrile is an example of such a compound.
Also preferred are compounds of formula I, in which
X signifies  greater than Cxe2x95x90 or xe2x95x90C less than  and R1 signifies unsubstituted phenyl or phenyl substituted in meta or para positions with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy or halogen.
An example of such a compound is 5-methyl-6-phenyl-3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-pyrazine-2-carbonitrile.
Further preferred compounds are those, in which
X signifies  greater than Cxe2x95x90 or xe2x95x90C less than  and R2 signifies xe2x80x94N(Re)(CHRf)m+1xe2x80x94ORg with Re,f,g signifying independently from each other hydrogen, lower alkyl or lower alkenyl.
5-(2-hydroxy-ethylamino)-3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-pyrazine-2-carbonitrile is an example of such a compound.
The term xe2x80x9clower alkylxe2x80x9d used in the present description denotes straight-chain or branched saturated hydrocarbon residues with 1-7 carbon atoms, preferably with 1-4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and the like.
The term xe2x80x9clower alkenylxe2x80x9d used in the present description denotes straight-chain or branched unsaturated hydrocarbon residues with 2-7 carbon atoms, preferably with 2-4 carbon atoms.
The term xe2x80x9clower alkoxyxe2x80x9d denotes a lower alkyl group as defined above linked to an oxygen group. Preferred alkoxy groups are methoxy or ethoxy.
The term xe2x80x9ccycloalkylxe2x80x9d denotes a saturated carbocyclic group containing from 3 to 6 carbon atoms, preferred are cyclopropyl, cyclopentyl or cyclohexyl.
The term xe2x80x9chalogenxe2x80x9d embraces fluorine, chlorine, bromine and iodine.
The term xe2x80x9cphenyl substituted in meta or para position with at least one substituent selected from the group consisting of lower alkyl, lower alkoxy or halogenxe2x80x9d means the homocyclic six membered aromatic ring which may be substituted by at least one substituent selected from the group consisting of lower alkyl, lower alkoxy or halogen in the para and/or meta positions, relative to the ring carbon that is attached to one of the carbons of the pyrazine ring of the compounds of formula I.
The compounds of formula I and their pharmaceutically acceptable salts can be manufactured by
reacting the compound of the formula 
with nucleophiles to obtain a compound of formula 
wherein R21 signifies xe2x80x94OR, xe2x80x94O(CHRa)m+1xe2x80x94OR, xe2x80x94NRc2, xe2x80x94NHxe2x80x94NRddxe2x80x22, xe2x80x94N(Re)(CHRf)m+1xe2x80x94ORg,
xe2x80x94N(Rh)(CHRi)m-pyridino, xe2x80x94N(Rj)(CHRk)nxe2x80x94(C3-C6)cycloalkyl, xe2x80x94N(Rl)(CHRm)m(CRn2)xe2x80x94NRo2, or
xe2x80x94N(Rp)(CHRq)m+1xe2x80x94NHxe2x80x94C(O)xe2x80x94O-lower alkyl as defined before, and, if desired,
converting a functional group of R21 in a compound of formula I-1 into another functional group to obtain another compound of formula I-1, and, if desired,
converting a compound of formula I-1 into a pharmaceutically acceptable salt; or reacting a compound of the formula 
wherein R22 signifies alkyl, with the compound of formula 
to obtain a compound of formula 
and, if desired,
converting a compound of formula 1-3 into a pharmaceutically acceptable salt; or reacting a compound of the formula 
wherein R5 signifies halogen, with the compound of formula 
to obtain a compound of formula 
and, if desired,
converting a functional group of R2 in a compound of formula 1-4 into another functional group to obtain another compound of formula I-4,
and, if desired,
converting a compound of formula I-4 into a pharmaceutically acceptable salt.
3-Methylsulfanyl-5-(1,2,4,5-tetrahydro-benzo- or thieno-azepin-3-yl)-[1,2,4]triazine-6-carbonitriles (I-2) are prepared by reaction of 3-(methylthio)-5-chloro-6-cyano-1,2,4-triazine (J. J. Huang, J. Org. Chem. 1985, 50, 2293-2298) with tetrahydro-benzo- or thieno-azepine compounds III, e.g. 2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (J. Heterocycl. Chem. 1971, 8(5), 779-83), in the presence of a base like triethylamine or ethyl-diisopropylamine in solvents like N,N-dimethylformamide, dimethylsulfoxide, methyl-ethylketone, ethanol, dioxane or tetrahydrofuran at temperatures between 10 and 50xc2x0 C.
Substitution of the Mexe2x80x94S-group in compound I-2 by optionally substituted N-nucleophiles can be performed in water, ethanol, N,N-dimethylformamide, dimethylsulfoxide, 1,2-dimethoxyethane, preferentially in dioxane at elevated temperatures, preferentially 100xc2x0 C to 160xc2x0 C.
Substitution of the Mexe2x80x94S-group in compound I-2 by optionally substituted O-nucleophiles can be performed in an inert solvent as ethers, like 1,2-dimethoxyethane or dioxane at temperatures between room temperature and 120xc2x0 C. after transformation of the corresponding alcohol into an alcoholate using a base like sodium hydride or potassium hydride.
The functionalization of the O- and N-nucleophiles can also serve as a protective function. Thus, modifications at the other part of the R21-substituent are allowed, e.g. removal of a N-protecting group, like the tert-butoxycarbonyl group, by methods well documented in the literature.
Compounds of formula I-1 can also be prepared by oxidation of the thioether I-2 to the corresponding sulfon according to known oxidative methods, e.g. by 3-chloroperbenzoic acid in dichloromethane, followed by treatment with thiolates, alcoholates, amines or aqueous base, e.g. like sodium carbonate or sodium hydrogencarbonate, thus yielding the group R21. 
Compounds of formula I-3 wherein R22 signifies lower alkyl can be prepared by reacting the intermediate II-1 with tetrahydro-benzo- or thieno-azepine compounds III, e.g. 2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (J. Heterocycl. Chem. 1971, 8(5), 779-83), in the presence of a base like triethylamine or ethyl-diisopropylamine in solvents like N,N-dimethylformamide, dimethylsulfoxide, methyl-ethylketone, ethanol, dioxane or tetrahydrofuran at temperatures between 10 and 50xc2x0 C.
The intermediate II-1 can be synthesized in analogy to the procedure as described in J. Org. Chem. 1972, 37 (24), 3958-3960, starting with the condensation of the corresponding amidrazones IV and methyl or ethyl oxomalonate V, followed by ammonolysis of the ester VI, and, finally, dehydration of the amide VII and substitution of the hydroxy group by chlorine (scheme 1). 
Compounds of formula 
are prepared by methods as shown in schemes 2, 3 and 4 and described in the following. 1,2-Dicarbonyl compounds VIII with R6 and R7 signifying both independently from each other hydrogen, optionally substituted phenyl, lower alkyl or lower alkenyl, react with 2-amino-malonic acid diamide IX as described in J. Amer. Chem. Soc. 1949,71,78-81, either in the presence of an aqueous base at temperatures between 0xc2x0 C. and 60xc2x0 C. or in the absence of a base in solvents like water or an alcohol at temperatures between room temperature and 120xc2x0 C. to form the two 3-oxo-3,4-dihydro-pyrazine-2-carboxylic acid amides Xa and Xb. Treatment of Xa and Xb either separately or as a mixture with phosphorus oxychloride and optionally additional phosphorus pentachloride in the presence of triethylamine or diethylaniline at temperatures between 40xc2x0 C. and 120xc2x0 C. give 3-chloro-pyrazine-2-carbonitriles II-3a and II-3b (scheme 2). 
3-Chloro-pyrazine-2-carbonitriles II-3a and II-3b react either separately or as a mixture with tetrahydro-benzo- or thieno-azepine compounds III or their hydrochlorides in solvents like N,N-dimethylformamide, acetonitrile, acetone or dimethylsulfoxide in the presence of a base like potassium carbonate or a tertiary amine as diisopropyl-ethylamine at temperatures between room temperature and 80xc2x0 C. to form the desired 3-(tetrahydro-benzo- or thieno-azepine-3-yl)-pyrazine-2-carbonitriles I-5a and I-5b, which can be separated by known methods such as chromatography or crystallization.
In an alternative method (scheme 3), bromopyrazine derivatives of formula II-4 are prepared by reacting O-tosylisonitrosomalononitrile XI with morpholino-enamines of formula XII with R11 signifying lower alkyl or lower alkenyl, in the presence of a base like pyridine, triethylamine or diisopropyl-ethylamine in aprotic solvents like ether, tetraydrofuran or N,N-dimethylformamide at temperatures between xe2x88x9220xc2x0 C. and 60xc2x0 C. to obtain (morpholino-alkenylimino)malononitriles XIII (Helv. Chim. Acta 1986, 69, 793-802). Treatment of the (morpholino-alkenylimino)malononitriles XIII with hydrobromic acid in acetic acid between room temperature and 80xc2x0 C. induces a cyclisation reaction leading to the bromopyrazines II-4 (Helv. Chim. Acta 1990, 73,1210-1214). 
Bromo-pyrazines II-4 react with tetrahydro-benzo or thieno-azepine compounds III or their hydrochlorides in solvents like N,N-dimethylformamide, acetonitrile, acetone or dimethylsulfoxide in the presence of a base like potassium carbonate or a tertiary amine like diisopropyl-ethylamine at temperatures between room temperature and 80xc2x0 C. to form the desired 3-(tetrahydro-benzo- or thieno-azepine-3-yl)-pyrazine-2-carbonitriles I-6. 3-(Tetrahydro-benzo- or thieno-azepine-3-yl)-pyrazine-2-carbonitriles of formula I-7 can be prepared according to scheme 4.
Diazotization of the 3-amino-5-chloro-2-cyano-pyrazine XIV (J. Org. Chem. 1975, 40, 2341-2347) with t-butyl-nitrite in solvents like acetonitrile or N,N-dimethylformamide in the presence of copper-(II)-bromide at temperatures between room temperature and 95xc2x0 C. gives the 3-bromo-5-chloro-2-cyano-pyrazine II-5. The 3-bromo-5-chloro-2-cyano-pyrazine II-5 reacts with one equivalent of a primary or secondary amine to two products, in which either the chloro-atom or the bromo-atom is replaced in the amine moiety. If the reaction is performed with a primary amine R8NH2 in a solvent like dioxane or tetrahydrofuran in the presence of a base like triethylamine or diisopropylethylamine, preferentially at room temperature, then compound II-6 with replaced chloro-atom can be obtained with reasonable selectivity. In a second analogous reaction, tetrahydro-benzo- or thieno-azepine compounds III or their hydrochlorides can then be reacted with II-6 in solvents like N,N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, acetone or dimethylsulfoxide and in the presence of a base like potassium carbonate or a tertiary amine like diisopropyl-ethylamine at temperatures between room temperature and 80xc2x0 C. giving compounds I-7. 
Optionally substituted 1,2,4,5-tetrahydro-benzo[d]azepine compounds III 
are prepared as described in the Eur. Pat. Appl. EP 1 074 549 A2 (2001). The 5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine with R3 and R4xe2x95x90H is known (J. Heterocyclic Chem. 1985, 22, 1011). Analogous 5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine compounds bearing substituents in the thiophene ring can be prepared in close analogy as outlined in scheme 5. Precursor acid chlorides XV bearing preferentially a tosyloxy protective function at the secondary nitrogen atom are cyclized in an inert solvent like 1,2-dichloroethane, dichloromethane or nitrobenzene in the presence of a Lewis acid catalyst like aluminium trichloride, tin tetrachloride or phosphorous pentachloride at temperatures between xe2x88x9240xc2x0 C. and 80xc2x0 C. to yield the protected ketones XVI. Hydroxy thieno[2,3-d]azepines XVII can be obtained by simultaneous reduction of the ketone function and removal of the N-tosyl protective function by treatment with sodium bis(methoxyethoxy)aluminium-hydride in toluene at reflux. The hydroxy thieno[2,3-d]azepines XVII can be further reduced to 5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepines XVIII with stannous chloride in acetic acid in the presence of hydrochloric acid at temperatures between room temperature and 100xc2x0 C. 
The methods for the preparation of compounds of formula I are described in more detail in examples 1 to 15.
The pharmaceutically acceptable salts can be manufactured readily according to methods known per se and taking into consideration the nature of the compound to be converted into a salt. Inorganic or organic acids such as, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I. Compounds which contain the alkali metals or alkaline earth metals, for example sodium, potassium, calcium, magnesium or the like, basic amines or basic amino acids are suitable for the formation or pharmaceutically acceptable salts of acidic compounds of formula I.
The compounds of formula I and their pharmaceutically acceptable salts are, as already mentioned above, metabotropic glutamate receptor antagonists and are therefore useful in the treatment or prevention of diseases which are mediated by metabotropic glutamate receptor antagonists. The compounds of formula I can be used for the treatment or prevention of acute and/or chronic neurological disorders, such as epilepsy, stroke, chronic and acute pain, psychosis, schizophrenia, Alzheimer""s disease, cognitive disorders, memory deficits and psychosis. Other treatable indications are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are Huntington""s chorea, ALS, dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by pharmaceutical compositions as well as conditions which lead to glutamate-deficient functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, dyskinesia and depression. The compounds are especially useful for the treatment of pain and migraine.
The compounds of the present invention are group I mGluR antagonists. Their pharmacological activity was tested using the following method:
Binding Assay for the Characterization of mGluR 1 Antagonistic Properties
Binding assay with tritiated 1-ethyl-2-methyl-6-oxo-4-(1,1,2-tritritio-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,6-dihydro-pyrimidine-5-carbonitrile (Eur. Pat. Appl. EP 1 074 549 A2): HEK 293 cells were transiently transfected with the rat mGluR1a receptor. The cells were collected and washed 3 times with PBS. The cell pellets were frozen at xe2x88x9280xc2x0 C. Membranes were prepared from HEK 293 cells transfected with the rat mGluR1a receptor and used in the binding experiments at 10 xcexcg proteins per assay after resuspension in a HEPES NaOH 20 mM, pH=7.4 binding buffer. 1-Ethyl-2-methyl-6-oxo-4-(1,1,2-tritritio-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,6-dihydro-pyrimidine-5-carbonitrile (S.A 33.4 Ci/mmol) was used at 3 nM final concentration. The incubation with variable concentrations of potential inhibitors was performed for 1 hour at room temperature, the incubate was then filtered onto GF/B glass fiber filter preincubated 1 hour in PEI 0,1% and washed 3 times with 1 ml of cold binding buffer. The radioactivity retained on the unifilter 96 was counted using a Topcount xcex2 counter. After correction for non specific binding the data were normalized and the IC50 value calculated using a 4 parameters logistic equation which was fitted to the inhibition curve.
The preferred compounds have an IC50 range of 0.001-10.0 xcexcmol/l (B-IC50).
In the table below are shown some specific activity data of preferred compounds:
The compounds of formula I and pharmaceutically acceptable salts thereof can be used as pharmaceutical compositions, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula I, but as a rule are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
In addition, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
As mentioned earlier, pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such pharmaceutical compositions which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day being preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg per day.
Finally, as mentioned earlier, the use of compounds of formula I and of pharmaceutically acceptable salts thereof for the production of pharmaceutical compositions, especially for the control or prevention of acute and/or chronic neurological disorders of the aforementioned kind, is also an object of the invention.
The following examples are provided for illustration of the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof.